This program project grant proposes the development of experimental and computational methodologies for use in structure-based approaches to drug design. The key program participants include two crystallographers, one theoretial biophysicist and one synthetic organic chemist. Compound design will focus on human purine nucleoside phosphorylase and the glutathione reductase and trypanothione reductase pair. Inhibitors of human purine nucleoside phosphorylase have potential application to AIDS by preventing the degradation of dideoxyinosine through conjunctive administration. Studies of glutathione and trypanothione reductases are aimed at developing new drugs for diseases caused by Leishmani, Plasmodia, Trypanosoma and other parasites. These studies may also suggest new approaches for the treatment of parasitic infection associated with AIDS. Other new methods of structure-based drug design will be evaluated using HIV protease and lysozyme, two extremely well characterized enzymes for which much structural information is available. Initial compound design will be based on characterization of the target binding site, interactive computer docking and energy minimization. Although detailed scientific studies will be performed by independent groups, compound design will be carried out using a team concept. The key participants and their groups will meet on a regular basis to discuss structural data, modeling studies and compound synthesis. Compounds will be considered and ranked by the team, then synthesized and evaluated using both biochemical and crystallographic techniques and the results will be compared to the predictions of the modeling studies. At the same time, new computational techniques based on renormalization group methods improved molecular dynamics and density functional theory will be developed to provide more accurate predictions for macromolecular systems. Once these techniques have been tested, they will be incorporated into the design process. In addition, various subjects such as fidelity of crystallographic information in the design process, importance of water structure, efficient data collection using synchrotron radiation, experimental analysis of accessible volume and prediction of conformational flexibility will be addressed.